BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia.
BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia.
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BET抑制作用是原发性B-培训急性淋巴细胞白血病的单一或联合治疗方法。
DOI：
10.1038/bcj.2013.24
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发表时间：
2013-07-19
影响因子：
12.8
通讯作者：
Stankovic, T.
中科院分区：
文献类型：
--
作者：
Da Costa, D.;Agathanggelou, A.;Perry, T.;Weston, V.;Petermann, E.;Zlatanou, A.;Oldreive, C.;Wei, W.;Stewart, G.;Longman, J.;Smith, E.;Kearns, P.;Knapp, S.;Stankovic, T.
儿科b前体ALL是一种高度可治愈的疾病，然而，一些患者的治疗耐药性和当前治疗的长期毒性作用使得需要更有针对性的治疗方法。我们研究了JQ1在儿科ALL中的细胞毒性作用，JQ1是一种高选择性抑制剂，可抑制转录调节因子、溴域和外端（BET）家族蛋白。我们发现，一组原发性ALL对JQ1有强烈的体外细胞毒性反应，与它们的预后特征无关，但依赖于MYC的高表达，并伴随着多种促生存途径的转录下调。与早期研究一致，JQ1诱导细胞周期阻滞。本研究表明，BET抑制还降低了ALL细胞中c-Myc蛋白的稳定性并抑制了DNA复制叉的进展。与c-Myc缺失和促生存通路下调一致，JQ1使原发性ALL样本对经典ALL治疗剂地塞米松敏感。最后，我们证明，无论是单独使用还是与地塞米松联合使用，JQ1都能降低ALL异种移植模型中的ALL生长。我们的结论是，靶向BET蛋白应该被视为治疗儿科ALL的一种新的治疗策略，特别是那些对标准治疗表现出次优反应的病例。
Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.
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